DESCRIPTION: Dietary methionine restriction (MR) produces a highly integrated series of biochemical and physiological responses that reduce adiposity, improve biomarkers of metabolic health and enhance insulin sensitivity. Our data make a compelling case that dietary MR acts through both centrally-mediated effects on energy balance, and direct effects on peripheral tissues that remodel lipid metabolism and enhance insulin sensitivity. We hypothesize that sensing of dietary MR is coupled to these responses through a combination of essential amino acid- dependent signaling and methionine-specific effects on cell glutathione which serve to enhance insulin signaling. We will use a combination of in vivo metabolic phenotyping and ex vivo biochemical analysis with loss of function animal models to examine the role of essential amino acid sensing in the respective responses to dietary MR. These studies will be complemented by a two-pronged in vivo and in vitro approach to establish the specificity of restricting dietary methionine versus other essential amino acids. The goal of this work is to identify the nutrient sensing and signaling systems which detect the restriction of methionine and translate this dietary modification into a highly integrated and beneficial set of physiological responses. The significant unanswered question addressed by this proposal is whether and how restriction of methionine provides significant additional benefits compared to restriction other essential amino acids. PUBLIC HEALTH RELEVANCE: Obesity and metabolic disease represent a growing health problem in the world and predispose affected individuals to developing more serious diseases including diabetes, heart disease, and stroke. Dietary methionine restriction produces a highly integrated series of biochemical and physiological responses that reduce adiposity, improve biomarkers of metabolic health and enhance insulin sensitivity. The pre-clinical studies proposed herein represent proof of concept testing and discovery to facilitate the development of diet-based approaches that will translate into effective treatments for metabolic disease.